JMJD2A

Official Full Name

lysine demethylase 4A

Organism

Homo sapiens

GeneID

9682

Background

This gene is a member of the Jumonji domain 2 (JMJD2) family and encodes a protein containing a JmjN domain, a JmjC domain, a JD2H domain, two TUDOR domains, and two PHD-type zinc fingers. This nuclear protein functions as a trimethylation-specific demethylase, converting specific trimethylated histone residues to the dimethylated form, and as a transcriptional repressor. [provided by RefSeq, Apr 2009]

Synonyms

KDM4A; JMJD2; JHDM3A; JMJD2A; TDRD14A;

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Detailed Information

Recent Research

Jumonji domain containing 2A (JMJD2A), also known as JHDM3 or KDM4A, is a transcriptional cofactor and enzyme that catalyzes demethylation of histone H3 lysines 9 and 36. Some reports show that JMJD2A is a novel N-CoR interacting protein, leading to transcriptional repression of downstream genes like ASCL2. Furthermore, this gene also reported to be a critical mediator of breast cancer proliferation, migration and invasion. JMJD2A can modify chromatin structure and function as a transcriptional repressor or activator. JMJD2A is reported to be widely expressed in diverse cancers, including lung carcinoma, colon cancer and breast cancer. Some studies indicate that JMJD2A is a potential oncogene and is overexpressed in human tumors. JMJD2A was overexpressed in endometrial carcinoma. Down-regulation of JMJD2A resulted in reduced endometrial carcinoma RL95-2 and ISK cell proliferation. JMJD2A is a promoter of endometrial carcinoma cell proliferation and survival, and is a potential novel drug target.

JMJD2A overexpression enhances cell motility and invasion and metastasis of bladder and colon carcinoma cells. One study has reported that JMJD2A gene expression is up-regulated in human prostate tumors, suggesting that JMJD2A may exert a tumor-promoting function. Endogenous JMJD2A regulates cell proliferation, apoptosis, invasion and metastasis in a variety of cancers. JMJD2A silencing suppressed proliferation of human endometrial carcinoma cell lines RL95-2 and ISK. Knockdown of JMJD2A inhibits migration and invasion of human endometrial carcinoma cells. JMJD2A silencing suppressed proliferation of human endometrial carcinoma cell lines RL95-2 and ISK. Knockdown of JMJD2A inhibits migration and invasion of human endometrial carcinoma cells. JMJD2A interacts with RNA polymerase I, associates with active ribosomal RNA genes and is required for serum-induced activation of rDNA transcription.

JMJD2A was positively correlated with Gleason score and metastasis in human prostate tumors. Overexpression of JMJD2A resulted in the development of prostatic intraepithelial neoplasia in mice, demonstrating that JMJD2A can initiate prostate cancer development. Moreover, overexpression of JMJD2A and the ETS transcription factor ETV1, a JMJD2A-binding protein, resulted in prostate carcinoma formation in mice haplodeficient for the phosphatase and tensin homolog (Pten) tumor-suppressor gene. Additionally, JMJD2A cooperated with ETV1 to increase expression of yes associated protein 1 (YAP1), a Hippo pathway component that itself was associated with prostate tumor aggressiveness. ETV1 facilitated the recruitment of JMJD2A to the YAP1 promoter, leading to changes in histone lysine methylation in a human prostate cancer cell line. Further, YAP1 expression largely rescued the growth inhibitory effects of JMJD2A depletion in prostate cancer cells, indicating that YAP1 is a downstream effector of JMJD2A. Taken together, these data reveal a JMJD2A/ETV1/YAP1 axis that promotes prostate cancer initiation and that may be a suitable target for therapeutic inhibition.

JMJD2A is highly expressed in breast cancer tissues. JMJD2A positively regulates the expression of ADAM12, CXCL5 and JAG1 genes through histone H3K9me3 demethylation. Expression of JMJD2A is positively correlated with progression of breast cancer and negatively with tumor suppressor ARHI. JMJD2A binds to ARHI promoter and negatively controls its promoter activity. ARHI reverses JMJD2A-induced tumor progression in vitro and in vivo. Therefore, JMJD2A could promote breast cancer progression through transcriptional repression of the tumor suppressor aplasia Ras homolog member I (ARHI). JMJD2A overexpression enhances estrogen-dependent transcription, and down-regulation of JMJD2A reduces breast cancer cell growth by forming a complex with endogenous estrogen receptor (ER) α in vivo.

References:

Li L L, et al. JMJD2A contributes to breast cancer progression through transcriptional repression of the tumor suppressor ARHI. Breast Cancer Res. 2014, 16(3):R56.
Wang H L, et al. Expression and effects of JMJD2A histone demethylase in endometrial carcinoma. Asian Pac J Cancer Prev, 2014, 15(7):3051-3056.
Salifou K, et al. The histone demethylase JMJD2A/KDM4A links ribosomal RNA transcription to nutrients and growth factors availability. Nature Communications, 2016, 7:10174.
Kim T D, et al. Histone demethylase JMJD2A drives prostate tumorigenesis through transcription factor ETV1. Journal of Clinical Investigation, 2016, 126(2):706-720.

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